Derivatives of 5-lower alkyl-sulfonyl anthranilic acid lower alkyl esters



United States Patent 5 Claims. (Cl. 260-470) This is a division of anapplication Ser. No. 218,537, filed Aug. 22, 1962, now U.S. 3,250,764.

The present invention relates to benzoic acid hydrazides which aresubstituted in the nucleus in Z-position by an amino group and in5-position by a sulfonyl group that is substituted by a lower aliphatichydrocarbon radical, as well as to salts of these compounds.

The nucleus of the new compounds may contain further substituents such,for example, as lower alkyl or alkoxy groups, especially thosecontaining 1-4 carbon atoms, such as the methyl-, ethyl-, norisopropylor butyl-, methoxy-, ethoxy-, propoxy-, or butoxy groups, orhalogen atoms, such as fluorine, chlorine, bromine or iodine or thepseudohalogen radical trifluoromethyl.

The hydrazine group is preferably unsubstituted, although it may besubstituted, for example, by aliphatic, araliphatic, heterocyclicaliphatic, aromatic or heterocyclic radicals or by acyl radicals of thesame kind, these substituent groups being bound to the hydrazine groupif desired by single or double linkages. Groups of this kind are, forexample, lower alkyl groups such, for example, as the above mentionedlower alkyls and alkylidenes such as ethylidene, propylidene-(l) or-(2), butylidene bound in any desired manner, phenylalkyl or-alkylidenes such as benzyl, phenylethyl or benzylidene,heterocyclylalkyl or -alkylidenes such as pyridylmethyl or -ethyl,pyridylmethylidene or furfurylidene, phenyl, pyridyl, furyl,tetrahydrofuryl or -pyranyl. As examples of acyl radicals, there arelower alkoxycarbonyl groups such as methoxyor ethoxycarbonyl, acetyl,propionyl, butyryl, pivalyl, valeroyl, caproyl, oenanthoyl, lauroyl,B-dimethylacryloyl, succinyl, phenyla-cetyl, cinnamoyl, benzoyl,phthaloyl, pyridoyl, furoyl, pyridylacetyl or thienylacetyl. Of theafore-mentioned groups, the aromatic rings may be further substituted bylower alkylor alkoxy groups, by the methylenedioxy group, by a halogenatom or by a trifluoromethyl-, nitroor amino group, for example, by adialkylamino group such as the dimethylamino- 0r diethyla-mino group.The aliphatic group may also contain a hydroxyl-, mercaptoor amino groupor a halogen atom.

The amino group present in the nucleus of the new benzoic acidhydrazides is preferably unsubstituted, although it may be monoordi-substituted, for example a monoor di-alkylamino group or ana-cylamino group, acyl groups being, for example those mentioned assuitable substituents for the hydrazine group.

The lower aliphatic hydrocarbon radicals of the sulfonyl group are, forexample, lower alkylor alkenyl groups such as the methyl-, ethyl-, norisopropy1-, or the straightor branch-chained butyl-, pentyl-, hexyl-,heptyl groups bound at any desired position or allylor methallyl groups.

The new compounds possess valuable, chemotherapeutic properties. Theyare especially valuable with regard to their action againstgram-positive and gram-negative pathogens, especially againststaphylococci and pneumococci, and against mycobacteria. They can,therefore, be

3,332,982 Patented July 25, 1 967 used pharmacologically in animals oras medicaments or prophylactic agents in the treatment of man andanimals. They may also be used as additives to animal feedstuffs and asintermediates in the manufacture of other valuable chemotherapeuticsubstances.

The compounds corresponding to the Formula I and salts thereof, in whichR, and R represent hydrogen atoms or lower aliphatic radicals, ortogether may represent a doubly bound aliphatic, cycloaliphatic orsaturated heterocyclic radical, such as an optionally substitutedalkylidene, cycloalkylidene or azacycloalkylidene, such aspiperidylidene radical or a hydrogen atom and an acyl radical of a loweraliphatic carboxylic acid, R represents a hydrogen atom or the acylradical of a lower aliphatic carboxylic acid, and R represents a loweralkyl group, and compounds of this type in which R represents a loweralkyl radical, are particularly effective.

The substituents of alkylidene radicals are, for example, tertiary aminogroups, such as lower dialkylamino, pyrrolidino, piperdino, morpholinoor optionally N-alkylated piperazino groups, those of cycloalkylideneradicals, for example lower alkyl radicals, those of azacycloalkylideneradicals for example lower alkyl radicals positioned at the nitrogenatom.

The outstanding members of the group of compounds corresponding totheformula I, are those in which R R and R represent a hydrogen atom andR, a lower alkyl group, and especially 5-isopropylsulfonyl-anthranilicacid-hydrazide and salts thereof, and those in which R and R representhydrogen and R and R lower alkyl radicals and such in which R and Rtogether represent a tertiary amino-lower alkylidene or an N-ioweralkylpiperidylidene radical and R and R have the meanings given above.

The new compounds are prepared according to methods in themselves known.Thus, for example, a 5-R-SO -2- aminobenzoic acid in which R is a loweraliphatic hydrocarbon radical, or a reactive, functional derivativethereof may be reacted with a hydrazine.

Reactive, functional derivatives of sulfonylbenzoic acids are, forexample, the halides thereof, such as the chloride or bromide, oresters, for example alkylor aralkyl esters, such as methyl-, ethylorbenzyl ester, or activated esters, such as the cyan-methyl ester.

The reaction of the above-mentioned compounds with the hydrazine, iscarried out by a method in itself known, above all in the presence of asolvent or diluent, in the presence or absence of a reactionaccelerator, at room temperature or preferably at a raised temperature,it necessary in a closed vessel under super-atmospheric pressure and/orunder an inert gas such, for example, as nitrogen. If desired, acondensing agent may be used, for

example, when an acid-halide is used, a basic condensing agent or anexcess of the hydrazine compound may be used.

Further substituents may be introduced into the compounds so obtained,by the usual methods, or substituents already present may be altered orremoved. Thus, for example, acylatable compounds obtained may beacylated by a known method, or acylated compounds may be hydrolyzed. Theother nitrogen substituents mentioned above may also be introduced, forexample, by reaction with corresponding carbonyl compounds. Groupswhich, for example, may be doubly bound to the hydrazine group, mayeither be reduced to singly bound groups or removed by hydrolysis.

The above-mentioned reactions are carried out in the usual manner, inthe presence or absence of a solvent or condensing agent and/orcatalyst, at subnormal, normal or raised temperatures, if desired in aclosed vessel and/ or in an inert gas atmosphere.

The sulfonyl-benzoic acids or their reactive, functional derivativesused as starting materials, which contain an amino-group or a halogenatom in the nucleus in the 2- position, and which may, if desired, alsocontain the other nuclear-substituents mentioned above, insofar as theyare new compounds, constitute a further provision of the presentinvention. They may be prepared according to methods in themselvesknown.

The invention also concerns modifications of the process, wherein acompound obtainable as an intermediate from any stage of the process isused as starting material, the missing stages being then carried out, orwherein a starting material is formed under the given reactionconditions or is used as a hydrate or salt thereof.

Depending upon the reaction conditions and starting materials used, thenew compounds are obtained in their free form, or in the form of theirsalts. The salts of the new compounds may be converted into the freecompounds by methods in themselves known, for example acid additionsalts may be converted by reaction with a Jase. Conversely, if a freebase should be obtained, it nay be converted into the salt thereof bytreatment with an inogranic or organic acid. Acid-addition salts may beprepared with the use especially of therapeutically suitable acids, forexample hydrohalic acids such, for example, as aydrochloric acid 'orhydrobromic acid, or perchloric acid, nitric acid, thiocyanic acid,sulfuric acid or phosphoric acid, or organic acids, such as formic acid,acetic acid, propionic acid, glycollic acid, lactic acid, pyruvic acid,oxalic acid, malonic acid, succinic acid, maleic acid, Eumaric acid,malic acid, tartaric acid, citric acid, ascorbic acid, hydroxymaleicacid, dihydroxymaleic acid, benzoic acid, phenylacetic acid,4-aminobenzoic acid, 4-hydroxy- )enzoic acid, anthranilic acid, cinnamicacid, mandelic acid, salicylic acid, 4-aminosalicylic acid,2-phenoxyben- :oic acid, 2-acetoxybenzoic acid, methane-sulfonic acid,thane-sulfonic acid, hydroxyethane-sulfonic acid, ben :ene-sulfonicacid, para-toluene-sulfonic acid, naphthaene-sulfonic acid, orsulfanilic acid, or methionine, trypto- )hane, lysine or arginine. Thesalts obtained may be nonoor poly-salts.

The new compounds may be used as medicaments n the form ofpharmaceutical preparations, which comrise the new compound in admixtureor conjunction vith an organic or inorganic, solid or liquidpharmaeutical excipient, that is suitable for local or enteral, orexample oral, or parenteral administration. These ex :ipients are, forexample, compounds which do not unlergo reaction with the new compounds,and are such, or example, as water, gelatine, lactose, starch, magneiumstearate, talc, vegetable oils, benzyl alcohols, gums,

olyalkylene glycols, White petroleum jelly, cholesterol u other knownmedicinal excipients.

The pharmaceutical preparations may be made in the orm, for example, oftablets, dragees or capsules, or in iquid form as solutions, suspensionsor emulsions. If .esired, they may be sterilized and/ or containassistants, uch as preserving, stabilizing, wettingor emulsifying gents,salts for regulating the osmotic pressure or bufers. They may alsocomprise other therapeutically valuble substances.

The new compounds may also be used in the breeding nd feeding ofanimals, in the form of feeding-studs, or s additives to animalfeeding-stuffs, and for this purpose, for example, the usual vehicles,diluents or fodders may be used.

The following examples illustrate the invention.

EXAMPLE 1 5 grams of 5-isopropylsulfonyl-anthranilic acid-methyl esterare boiled under reflux with 50 cc. of hydrazine hydrate, for fourhours. The mixture is then evaporated to dryness under vacuum, theresidue is triturated with water, and then filtered to isolate thecrystalline precipitate so obtained. By re-crystallization from alcohol,5- isopropylsulfonyl-anthranilic acid-hydrazide of the formula isobtained as white crystals melting at 178-179 C.

EXAMPLE 2 5 grams of 5-methylsulfonyl-anthranilic acid methyl ester areboiled under reflux for 3 hours with 50 cc. of hydrazine hydrate. Thereaction mixture is then evaporated to dryness under reduced pressure,the residue taken up in 20 cc. of water and adjusted to pH 7 with 2N-acetic acid. On cooling, a crystalline precipitate settles out, whichis recrystallized from water to yield 5- methylsulfonyl-anthranilic acidhydrazide of the formula (I) O NHNH:

CHsOzS- in the form of white crystals melting at 172-175 C.

EXAMPLE 3' (I) O NHNHa CzHuOz S- in the form of white crystals meltingat 171-175 C.

EXAMPLE 4 8 grams of S-n-butylsulfonyl-anthranilic acid methyl ester areboiled under reflux for 2 /2 hours with cc. of hydrazine hydrate. Thereaction mixture is evaporated to dryness under reduced pressure, 30 cc.of water are added to the residue and the reaction solution is adjustedto pH 7 with 2 N-hydrochloric acid. On trituration the oily masssolidifies to form a crystalline precipitate which is recrystallizedfrom a mixture of ethanol and water to yield5-n-butylsulfonyl-anthranilic acid hydrazide of the formula in the formof white crystals melting at 156l58 C.

The starting materials used in the preceding examples may 'be prepared,for example as follows:

(a) 2-chl0r0-5-alkylsulf0nyl-benzo ic acids 127.5 grams of2-chloro-5-chlorosulfonyl-benzoic acid are added in small portions, withstirring, to a solution of 378 grams of sodium sulfite (Na SO -7H O) in500 cc. of water. At the same time 145 cc. of 10 N-sodium hydroxidesolution are added so that the reaction solution always shows a pH of 9.By means of ice-cooling care is taken that the internal temperaturenever rises above 25 C. After adding the last portion of thesulfochloride, the reaction mixture is stirred for 4 hours at roomtemperature. The reaction solution is cooled to C. and then treated with220 cc. of concentrated hydrochloric acid while cooling with ice, awhite precipitate forming. After the filtered crude sulfinic acid hasbeen dissolved in 100 cc. of water and 200 cc. of ethanol, the reactionsolution is adjusted to pH 9 with 10 N-sodium hydroxide solution, Whilestirring; 200 grams of ethyl bromide are added and the whole boiledunder reflux for 36 hours. During this time the reaction solution iskept constantly weakly alkaline by the addition of small portions of 10N-sodium hydroxide solution. The bulk of the ethanol is removed underreduced pressure and the aqueous alkaline solution acidified with theconcentrated hydrochloric acid while cooling with ice. The precipitatedsolid substance is filtered off, recrystallized from a mixture ofethanol and water to yield 2-chloro-5-ethylsulfonyl-benzoic acid in theform of white crystals melting at 151-153" C.

In an analogous manner there may be obtained 2-chloro--isopropylsul-fonyl-ibenzoic acid melting at 132- 134 C.,2-chloro-S-methylsulfonyl-benzoic acid melting at 182-185 C. and2-chloro-5-n-butyl-sulfonylbenzoic acid melting at 137-l39 C.

(b) 5-alkylsulfonyl-anthranilic acids 6 2 grams of2-chloro-S-methyl-sulfOnyl-benzoic acid of M.P. 182185 C. are heated ina pressure vessel with 700 cc. of concentrated ammonia solution and 1.5grams of copper powder for 12 hours at 125-130 C. The cooled, filteredammonia solution is introduced into concentrated hydrochloric acid withstirring and ice-cooling until the reaction mixture is finally justweakly acid to Congo red. The crystalline precipitate which has formedis filtered off and recrystallized from a mixture of ethanol and waterto yield 5-methylsulfonyl-anthranilic acid melting at 234-235 C.

In an analogous manner there may be obtained5-isopropylsulfonyl-anthranilic acid melting at 2l3-216 C.,5-ethylsulfonyl-anthranilic acid melting at 209-2l1 C. and5-n-butylsulfonyl-anthranilic acid melting at 175- 178 C.

(c) 5-alkylsulf0nyl-anthranilic acid methyl esters 30 grams of5-methylsulfonyl-anthranilic acid are introduced intoa solution of 25cc. of sulfuric acid monohydrate in 90 cc. of absolute methanol and thewhole is boiled under reflux for 16 hours. The cooled reaction solutionis then poured on to ice, extracted with methylene chloride, the organiclayer washed with sodium bicarbonate solution and after being dried overmagnesium sulfate evaporated under reduced pressure. By recrystallizin'gthe solid residue from a mixture of isopropanol and petroleum etherthere is obtained S-methylsulfonyl-anthranilic acid methyl ester meltingat 139- 145 C.

In an analogous manner there maybe obtained5-isopropylsulfonyl-anthranilic acid methyl ester melting at 142-144 C.,S-ethylsulfonylanthranilic acid methyl ester melting at -94 C. and5-n-butylsulfonyl-anthranilic acid methyl ester (oil).

EXAMPLE 5 7 grams of 2-ethylamino-S-methyl-sulfonyhbenzoic acid methylester are boiled under reflux together with 70 cc. of hydrazine hydratefor 2 hours. The reaction mixture is evaporated to dryness under reducedpressure, the residue is triturated with water and the crystallineprecipitate filtered oif, recrystallized from a mixture of ethanol andwater to yield 2-ethylamino-5-methylsulfonyl-benzoic acid hydrazide ofthe formula in the form of white crystals melting at 168-171" C.

The 2 ethylamino-S methyl sulfonyl benzoic acid methyl ester used asstarting material may be prepared as follows:

70 grams of 2-chloro-S-methyl-sulfonyl-benzoic acid are heated in apressure vessel with 700 cc. of an aqueous ethylamine solution of 25%strength and 1.5 grams of vcopper powder for 14 hours at -130 C. Thereaction mixture is cooled to room temperature, filtered and thefiltrate poured with stirring and ice-cooling into concentratedhydrochloric acid until the reaction mixture is finally just weakly acidto Congo red. The precipitate formed is filtered 0E and recrystallizedfrom a mixture ,Of ethanol and water to yield 2-ethylamino-5-methyl-EXAMPLE 6 A solution of 2 grams of N-methyl-piperidone-( l) in 5 cc. ofabsolute alcohol is added to 2.29 grams of 5-methylsulfonyl-anthranilicacid hydrazide in 70 cc. of absolute alcohol with stirring, and thewhole is boiled under reflux for 16 hours. The reaction mixture is thenevaporated to dryness and the residue recrystallized from alcohol. Thereis obtained 5-methyl-sulfonyl-anthranilic'acid-N-(N-methyl-piperidylidene-(4))-hydrazide of the formula CoNHNO-orn CHQSOQ melting at 202-203 C.

The hydrochloride of the above base is prepared as follows: A suspensionof 1.62 grams of the base in 25 cc. of absolute alcohol is treated withheating with the calculated quantity of hydrogen chloride in alcohol,the whole passing into solution. After a short time the hydrochlorideprecipitates in the form of white crystals melting at 224-227 C.

7 8 What is claimed is: References Cited 1. A benzoic acid ester, saidester being derived fIOIn UNITED STATES PATENTS a member selected fromthe group consisting of a lower alkanol, an aryl-lower alk-anol and acyan-lower alkanol, 3124 610 3/1964 Larsen 260 470 XR which issubstituted in 2-positi0n of the benzene nucleus 5 by a member selectedfrom the group consisting of amino FOREIGN PATENTS and lower alkyl aminoand in 5-position by lower alkyl- 586,999 4/1957 Great Britain sulfmlyl-864,829 4/1961 Great Britain.

2. A S-lower alkylsulfonyl-anthranilic acid methylester.

3. 5-isopropylsulfony1-anthranilic acid methylester. 4.5-ethylsulfonyl-anthranilic acid methylester. 10 LORRAINE WEINBERGERExamine"- 5. S-n-butylsulfonyl-anthranilic acid methylester. RICHARD K.JACKSON, Examiner.

1. A BENOZIC ACID ESTER, SAID ESTER BEING DERIVED FROM A MEMBER SELECTEDFROM THE GROUP CONSISTING OF A LOWER ALKANOL, AN ARYL-LOWER ALKANOL ANDA CYAN-LOWER ALKANOL, WHICH IS SUBSTITUTED IN 2-POSITION OF THE BENZENENUCLEUS BY A MEMBER SELECTED FROM THE GROUP CONSISTING OF AMINO AND LOWRALKYL AMINO AND IN 5-POSITION BY LOWER ALKYLSULFONYL.